Jean-Francois Pittet, M.D.

Depts of Anesthesia and Surgery

Cardiovascular Research Institute
University of California San Francisco

Acute Traumatic Coagulopathy

 Plan

1. Description of the coagulation system

2. Post-traumatic coagulopathy: mechanisms

3. Mouse model of trauma-hemorrhage

4. Therapeutic approach of post-traumatic coagulopathy

1. Coagulation in the perfect world
 Initiation phase
Trauma,
induces the initiation
of coagulation

Tissue factor (TF) is

exposed and binds to
FVIIa or FVII which is
subsequently
converted to FVIIa

The complex between

TF and FVIIa activates
FIX and FX
Hypoxia
FXa binds to FVa
on the cell surface
Amplification phase

The FXa/FVa complex

converts small amounts
of prothrombin into
thrombin

The small amount of

thrombin generated
activates FVIII, FV, FXI
and platelets locally.

FXIa converts FIX

to FIXa

Activated platelets
bind FVa, FVIIIa
and FIXa
 Propagation phase
The FVIIIa/FIXa
complex
Fibrin
activates FX on the
surfaces of activated
platelets

FXa in association
with FVa converts
large amounts of
prothrombin into
thrombin creating a
thrombin burst.

The thrombin burst

leads to the formation
of a stable fibrin clot.
 2. Coagulopathy in the wild
Mechanisms of Acute Traumatic
Coagulopathy
 The Lethal Triad
Bloody Vicious Cycle
Severe Trauma

Bleeding

Tissue Hypoxia Fluid Replacement RBC Transfusion

Acidosis Dilution Hypothermia

Coagulopathy
 The Lethal Triad
Bloody Vicious Cycle
Severe Trauma

Bleeding

Tissue Hypoxia Fluid Replacement RBC Transfusion

Acidosis Dilution Hypothermia

Coagulopathy
Occurs
Occursat
atpH
pH<<7.1
7.1 Seen
Seenonly
onlyat
at<33C??
<33C??
Not
Notreversed
reversedwith
withpH
pHneutralization
neutralization ininonly
only9%
9%pts
pts

IV
IVFluids
Fluids
Acute Traumatic Coagulopathy
Study at Royal London Hospital
Brohi et al J Trauma 54:11271130, 2003

1088 trauma patients admitted over 6-year period

Median time Incident Hospital Admission: 72 minutes

24.4% arrived to the Hospital coagulopathic

No coagulopathy: 10.9% mortality

Coagulopathy: 46% mortality
 Posttraumatic Coagulopathy
Death
MODS
EAC SAC
endogenous systemic
acutecoag. acquired
coag.
Recover

Injury
Coag Recover
Hemorrhage

SAC Recovery
systemic
acquiredcoag.

Death
MODS

TimeafterInjury
 Possible Mechanisms for EAC

Impaired thrombin formation?

Coagulation factor deficiency?

Activation of the natural anticoagulant pathways (Protein C,

Tissue Factor Pathway Inhibitor and antithrombin)?
Acute Traumatic Coagulopathy

Study at San Francisco General Hospital

Ann Surg 245:812-818, 2007

209 severely traumatized patients admitted to SFGH

Median time injury hospital admission: 28 minutes

18% of the patients had a systolic BP < 100 mm Hg

27% of the patients had an arterial base deficit > 6
Acute Traumatic Coagulopathy: Role of
Hypoperfusion
A PTT (s) B PT (s)
60
*
18 *
50 16
40 14
30 12
20 10
2.1 2.2-4.1 4.2-7.6 7.7 2.1 2.2-4.1 4.2-7.6 7.7
Base Deficit (mEq/l) Base Deficit (mEq/l)

C PTT (s) D PT (s)

+ +
80
BD -6
* 22
20 BD -6 *
60 BD > -6 18 BD > -6
16
40 14
12
20 10
<2 2-4 >4 <2 2-4 >4
Prothrombin fragments 1+2 Prothrombin fragments 1+2 (nM)
 Acute Traumatic Coagulopathy:
Role of Protein C Pathway
A PTT (s) B PT (s)
60 20
* 18 *
16
40
14
12
20 10
102 79-101 58-78 57 102 79-101 58-78 57
Protein C (%) Protein C (%)

C aPC (ng/ml) D Factor V (%)

140
2.5
2
* 120
100
1.5 80
1 60
0.5 40
20
0 0
BD -6 BD > -6 0 20 40 60 80 100 120 140 160
Protein C (%)
 Acute Traumatic Coagulopathy:
Effect on Fibrinolysis

A PAI-1 (AU/ml) B D-Dimers (ng/ml)

30 16
25
12
*
20
15 8
*
10
5 * 4
0 0
102 79-101 58-78 57 102 79-101 58-78 57
Protein C (%) Protein C (%)
 Activated protein C pathway

Thrombin binds
Fibrin Thrombomodulin
D-Dimers

The complex
Thrombin-
Thrombomodulin
activates Protein C
APC
HYPOPERFUSION
APC decreases
FVIIIa and FVa
and induces
PC D-dimers production
EPCR
 Acute Traumatic
Coagulopathy (EAC)
Early coagulopathy after trauma and shock:

- Independent of traditional iatrogenic causes.

- Associated with tissue hypoperfusion.
- Secondary to the activation of the Protein C pathway.
- Associated with a derepression of fibrinolysis.
- Hypoperfusion is necessary for TBI patients to be
coagulopathic early after trauma.
 3. Mouse Model of
Trauma-Hemorrhage
 Animal Model of Trauma/Hemorrhage

Soft-Tissue Trauma
Hemorrhagic shock:
Non-ventilated, fixed-pressure.
Blood withdrawn via vascular line.
MAP 35 +/- 5mmHg x 60 min.
Fluid Resuscitation:
LR @ 2x shed blood volume
+ shed blood
Acute Traumatic Coagulopathy in Mice
Acute Traumatic Coagulopathy is Mediated by
aPC Anticoagulant Function

mAb 1591 anticoagulant

aPC
cytoprotective
 Inhibition of the Cytoprotective Domain of Protein C
Causes Diffuse Intravascular Coagulation Lung Injury
mAb 1609 anticoagulant
aPC
cytoprotective

A. Control mAb B. mAb 1609

Perivascular Hemorrhage

Pulm. Artery
with Thrombus

.
Acute Traumatic Coagulopathy in Mice:

mAb 1609 anticoagulant

aPC
cytoprotective
 Summary

* First Animal Model of Acute Traumatic Coagulopathy

- Mimics human response to trauma/hypoperfusion

* Role of Activated Protein C in Trauma/Hypoperfusion

aPC function Acute Traumatic SURVIVAL/

REQUIRED for Coagulopathy Prevention of DIC

Anticoagulant + -

Cytoprotective - +
 Clinical Implications

1.Inhibition of anticoagulant function of Protein C could

become a NEW, mechanistic treatment for Acute
Traumatic Coagulopathy in trauma patients.

2. Role of protein C in organ dysfunction in traumatic

shock: recombinant mutant non-anticoagulant protein
Cpotential treatment in humans?
4. But what should we do?
Focus on Coagulopathy

Early use of blood products

Massive blood loss:
Give products in a ratio of
PRBC:FFP:platelets 1:1:1 ?
 Massive Transfusion

Traditionally, FFP & platelet

concentrates are given as needed
---> However:
1. The coagulation lab is slow!
2. Patients already have a coagulopathy,
why wait?
Prevent the Lethal Triad

1.Keep warm:
All fluids through warmers
Keep the OR warm X
Hypothermia

2.Minimalize crystalloid:
Continue a 1:1:1 resus. X
Dilution

3.Reduce Shock:
Damage control surgery X
Acidosis

4.Break the cycle: Bleeding

Consider other components
X
Coagulopathy
Thank You
 Acknowledgments
Mitchel J. Cohen
Michael West Greg Stahl
Karim Brohi Chuck Esmon
Natasha Bir John Griffin
Brian Chesebro Ken Mann
Michel Carles Adam Arkin
Pamela Rahn John Doyle
Marybeth Howard John Holcomb

Funded by Grants from NIH (NIGMS)